Retroviruses and Novel Drugs

Biography

Biography: Harold C. Smith

Abstract

Camptothecin (CPT) is a natural product discovered to be active against various cancers through its ability to inhibit Topoisomerase 1 (TOP1).  CPT analogs also have anti-HIV-1 (HIV) activity that has been previously shown not to depend on inhibition of TOP1.  We show that anti-cancer inactive CPT analogs inhibit HIV infection by disrupting homo-oligomerization of an HIV auxiliary protein known as viral infectivity factor (Vif). Antiviral activity depended on the expression of the cellular viral restriction factor known as APOBEC3G (A3G) that, in the absence of functional Vif, has the ability to hypermutate HIV proviral DNA during reverse transcription. Our studies demonstrate that a non-toxic CPT analog (i) prevented Vif multimerization and Vif-dependent A3G degradation, (ii) increased A3G in pseudotyped HIV viral particles along with A3G signature hypermutations in viral genomes, and (iii) possessed an A3G-dependent and broadly neutralizing antiviral activity against seventeen HIV clinical isolates from Groups M (subtypes A-G), N, and O as well as seven single and multi-drug resistant strains of HIV. Medicinal chemistry and structure activity relationship (SAR) efforts further identified a more potent analog that reached a therapeutic index of greater than 1,000 against live HIV subtype A following a single dose in 7-day spreading infections.  We propose that CPT analogs not active against TOP1 have an antiviral mechanism through Vif antagonism that enables A3G-dependent hypermutation of HIV.